Transdermal therapeutic system for the administration of physostigmine to the skin and process for the production thereof

ABSTRACT

A transdermal therapeutic system for the administration of physostigmine to the skin, consisting of a backing layer impermeable to active substance, a pressure-sensitive reservoir layer containing 40 to 90%-wt. polymeric material and 0.1 to 20%-wt. physostigmine base or one of the pharmaceutically acceptable salts thereof, and of a detachable protective layer covering the reservoir layer, comprises in its reservoir layer acrylate- and/or methacrylate-based polymeric material and 0.1 to 40%-wt. of a softener containing the hydroxyl group with an HLB value between 1.1 and 12.0.

This application is a 371 of PCT/EP93/02970, filed Oct. 27, 1993.

The invention relates to a transdermal therapeutic system containingphysostigmine as active component, and to a process for the productionthereof.

The application of physostigmine, for example for the treatment ofAlzheimer's disease has been described in the literature several times,whereby the efficacy of the substance was judged differently. Since thealkaloid exhibits a high first pass effect--the bioavailability ofphysostigmine after oral administration is in the range of 5%--thediffering results must be attributed to different forms of application.

DE-OS 35 28 979 describes a composition which in addition tophysostigmine contains a medium-chain carboxylic acid; this compositioncan be applied on a bandage, an insert or a compress, which are appliedby means of a dressing. With this kind of application, which is not aTTS per se, it is intended to provide the bandage, compress or insertwith an inner reservoir layer, an impermeable protective barrier foil oran impermeable protective film and to apply a diffusion controllingmembrane between the reservoir and the skin. Neither the diffusioncontrolling membrane nor the protective foils are described in detail.The carboxylic acids are explicitly mentioned to be effective carriersfor the administration of the pharmaceutic through the skin whichotherwise would not be able to penetrate through the skin barrier.However, this statement is not tenable from the scientific point ofview. DE-PS 36 06 892 describes a retarded application of physostigmineand other active substances, which application may be carried outtransdermally. A special formulation is not disclosed. What is more,reference is made to a pre-described formulation (U.S. Pat. No.3,921,363).

A further publication describing the application of physostigmine is WO91/15176. This publication does not go beyond the teaching of the GermanPatent DE 38 43 239 discussed hereinbelow. Apart from the only vaguestatements concerning the transdermal therapeutical systems, neither ofthe two publications mentioned hereinabove deal with the instability ofphysostigmine, which instability was realized very early. In thisrespect, however, reference may be made, for example, to the followingliterature dealing with the instability of physostigmine: (Eber, W.,Pharmaz. Ztg. 37, 483 (1888), Herzig, J., Mayer, H., Mh. Chem. 18, 379(1897); Herzig, J., Lieb, H., ibidem 39, 285 (1918); Salway, A. A., J.Chem. Soc. (London) 101, 978 (1912)).

Owing to a rapid decomposition of the active substance, this instabilityseverely limits the use of physostigmine in pharmaceutics.

The problem of the rapid decompostion of physostigmine in a TTS is alsodealt with in DE 38 43 238 and DE 38 43 239. The TTS described in DE 3843 239 exclusively contains lipophilic softeners, whereas the systemdescribed in DE 38 43 238, apart from lipophilic softeners, containscarboxylic acids with rather long chains, viz oleic acid or undeceneacid, as solvents for physostigmine. These fatty acids, as well, arelipophilic substances. Thus, the two systems have in common thatphysostigmine is released to the skin from a lipophilic matrix securingthe stability of the active substance.

Surprisingly, it was found by way of controls that TTS preparedaccording to the teachings of the patent specifications DE 38 43 238 andDE 38 43 239 do not satisfactorily meet the strict requirements whichmust be applied to the self-adhesiveness of a TTS. Tests in which theTTS were worn brought the result that in the case of some of the testpersons the TTS, after having been worn for only 8 hours, did no longeradhere with their entire surface. After 24 hours, 10% of the testpersons had lost the TTS, and in the case of 15% of the test personsthere was no longer an all-over skin contact. Only in the case of 75% ofthe test persons was the adhesive behaviour of the TTS satisfactory.However, TTS which adhere only with 75% of the test persons or patientswithout giving cause for complaints do not fulfil the strictrequirements that must be applied to therapeutic systems. By definition,a transdermal therapeutic system contains one or more drugs which arereleased at a pre-determined rate, continuously, over a pre-determinedperiod of time, to a pre-determined application site ("Heilmann, Klaus:Therapeutische Systeme--Konzept und Realisation programmierterArzneiverabreichung", 4th edition, Ferdinand Enke Verlag Stuttgart,1984, p. 26). Without permanent skin contact over the predeterminedperiod of time, physostigmine cannot be released in a controlled manner,which puts the desired therapy in question or seriously endangers it,respectively.

It is known to the man skilled in the art that the adhesive behaviour ofa TTS improves with increasing polarity of the softener incorporatedinto the system.

In the following experimental part it will be shown that--although thereare exceptions--the adhesive force of the TT systems manufactured inaccordance with the invention is the greater, the greater thehydrophilicity of the matrix. As a measure for the hydrophilicity, thehydrophilicity of the softeners employed, viz that of alcohols, wasused.

A further measure for the hydrophilicity of the softeners is their HLBvalue, which may be calculated according to the following formula:##EQU1## (quotation from Voigt, Rudolf: Lehrbuch der pharmazeutischenTechnologie, 3rd revised edition, Verlag Chemie, Weinheim, New York1979, p. 352)

The HLB values of the softeners are shown in Table 5.

Since softeners split physostigmine hydrolytically, it is necessary toformulate such matrices as are, on the one hand, hydrophilic, owing tothe use of special polar softeners, and which, on the other hand,prevent the hydrolysis of the active substance owing to the provision ofparticularly suitable polymer components.

It is thus the object of the invention to provide a TTS releasingphysostigmine or one of the pharmaceutically acceptable salts thereofover a period of time of at least 12 hours, in a controlled manner,securing a durable fixation of the plaster, over its entire surface, tothe human body, and at the same time ensuring that the physostigminecontained in the system is not decomposed in a manner altering thetherapeutic effect.

This object is achieved in accordance with the invention by means of atransdermal therapeutic system according to the invention.

In this connection, the backing layer impermeable to active substancemay consist of flexible or inflexible material. Materials which can beused for the production of said layer are polymer films or metal foils,such as aluminium foil, used singly or coated with a polymer substrate.Also, textile fabrics may be used, if the components of the reservoircannot penetrate through the same owing to their physical properties. Ina preferred embodiment, the backing layer is a composite material madeof an aluminized foil.

A process for the production of the TTS is also provided.

The reservoir layer consists of a pressure-sensitive polymer matrix andcontains the active substance physostigmine or the pharmaceuticallyacceptable salts thereof, the softener and, as may be required from caseto case, additives.

When selecting the substances for the construction of the reservoir, thefollowing requirements must be simultaneously fulfilled:

The physostigmine, which is comparatively unstable, must not be split byhydrolysis nor attacked by oxidation during storage or therapy.

The reservoir layer must exhibit good adhesive behaviour towards theskin over the entire period during which the TTS is to be worn, at least12 hours.

These conditions are surprisingly fulfilled by combining the basepolymers and softeners described according to the invention, theselection of the base polymer being dependent on the chemical andphysical properties of the physostigmine and having to fulfil therequirement that the matrix be sufficiently hydrophilic to secureadhesive force when the TTS is being worn.

In this connection, the invention starts out from the finding that it isnot the polymers but the softeners that split physostigminehydrolytically. For this reason, the hydrophilicity of the softenersmust not exceed a certain limit.

Solvents such as, for example, methanol, ethanol and isopropanol, whichare not softeners in the sense of the invention, admittedly have HLBvalues within the limits of the invention; however, they do cause thecleavage of physostigmine. For this reason, they must not be used in thereservoir layer of the matrix.

Alcohols having extremely low HLB values, e.g. heptadecanol, nonadecanoland eicosanol, are not capable of splitting physostigmine, it is true,but they lead to a poorer adhesive behaviour of the system, and thusconstitute no improvement over the triglycerides of the medium-chainfatty acids.

The hydrophilicity of the matrix required for the active substance flowthrough the skin must consequently be realized by using polymers havingpolar functional groups, such as hydroxyl, carbonyl, carboxyl or aminogroups.

Suitable polymers are, for example, polyacrylates or polymethacrylateshaving the aforementioned polar functional groups.

Without limiting the invention, acrylate-based acrylate copolymers of2-ethylhexyl acrylate, vinyl acetate and acrylic acid with or withouttitanium or aluminium chelate esters, respectively, are preferred.Preferred methacrylates are copolymers on the basis ofdimethylaminoethyl methacrylates and neutral methacrylic esters.

Examples for softeners according to the invention are higher alcohols,as they are, on the one hand, sufficiently hydrophile to form therequired "hydrophile matrix" with the above-described polymers, but, onthe other hand, are not polar enough to split physostigmine in thesysteme via alcoholysis. Linear or branched, saturated or unsaturatedalcohols with 6 to 20 carbon atoms have proved particularly successfull.

The kind of possible other additives is dependent on the polymer,softener and active substance employed: According to their function,they can be divided into tackifiers, stabilizers, carriers, diffusionand penetration regulating additives, or fillers. Without limiting theinvention, as fillers, polymers selected from the groups of thepolyvinyl pyrrolidones are mentioned. Other physiologically acceptablesubstances suitable for this purpose are known to the man skilled in theart.

The removable protective layer, which is in contact with the reservoirlayer and is removed prior to application, consists, for example, of thesame materials as are used for the manufacture of the backing layer,provided that they are rendered detachable, for example, by way of asilicone treatment.

Other detachable protective layers are, for example,polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride,and the like. Where the laminate according to the invention is dividedinto sizes (plasters) suitable for therapy, the dimensions of theprotective layer may have a protruding end, so that they may be strippedoff the plaster more easily.

Proof of the stability conditions of physostigmine: In comparisonexample 1, triglycerides of medium-chain fatty acids, DAB 9 =the GermanPharmacopoeia, 9th edition! (neutral oil), HLB value 1, are used assofteners, since these softeners, according to the teaching of DE 38 43239 guarantee the stability of physostigmine. This can be proved by wayof experiments. In the other examples, softeners selected from thecompound group of alcohols (branched or linear, saturated orunsaturated) with 6 to 20 carbon atoms are used. Surprisingly, in thiscase also, the stability of the physostigmine in the TTS is successfullyproved by means of experiments although in a compatibility testphysostigmine is hydrolytically split by these compounds. For thispurpose, samples of about 50 mg physostigmine base and about 100 mgalcohol each were stored for three weeks, at 40° C. in an HPLC vessel,under exclusion of light and air.

Subsequently, 1 ml chloroform is added to each of the samples and thecolour is assessed. Thereafter, the samples were examined by thin-layerchromatography.

The TLC conditions are as follows:

    ______________________________________                                        Absorbent:    silica gel TLC glass plate 60 F 254                             Solvent:      chloroform:acetone:diethylamine 5:4:1                           Chamber saturation:                                                                         2 h                                                             Flow time:    35 min                                                          Amount applied:                                                                             5 μl                                                         Detection:    1. UV light 254 nm                                                            2. iodine chamber                                               ______________________________________                                    

The results are shown in the following Table 1.

                  TABLE 1                                                         ______________________________________                                                                   TLC-Evaluation:                                                               Decomposition                                      50 mg Physostigmine +      product                                            100 mg "softener"                                                                            Colour      detectable                                         ______________________________________                                        1.    triglycerides of                                                                           colourless  -                                                    medium-chain                                                                  fatty acids                                                             2.    methanol     dark red    ca. 20%                                        3.    ethanol      dark red    ca. 15%                                        4.    isopropanol  dark red-red                                                                              ca. 15%                                        5.    1-hexanol    dark red-red                                                                              +                                              6.    1-heptanol   red         +                                              7.    1-octanol    bright red  +                                              8.    1-nonanol    bright red  +                                              9.    1-decanol    bright red  +                                              10.   1-undecanol  bright red  -                                              11.   1-dodecanol  bright red  +                                              12.   1-tetradecanol                                                                             colourless- in traces                                                         bright red                                                 13.   1-pentadecanol                                                                             colourless- in traces                                                         bright red                                                 14.   1-heptadecanol                                                                             colourless  in traces                                      15.   1-nonadecanol                                                                              colourless  -                                              16.   1-eicosanol  colourless  -                                              17.   2-octyldodecanol                                                                           colourless  -                                                    (1)                                                                     18.   oleyl alcohol                                                                              yellow      -                                              ______________________________________                                    

Evaluation of the colours:

Since the decomposition products of physostigmine are coloured, onlythose solutions can be considered stable which remain colourless (Nos. 1and 14-17). At the same time, the degree of decomposition can beinferred from the intensity of the change in colour.

The TTS were produced according to the following method: The transdermaltherapeutic system according to the invention is manufactured preferablyby homogeneously admixing the active substance with the components ofthe pressure-sensitive reservoir layer, optionally in solution, and isspread onto the backing layer impermeable to active substance,whereafter the solvent or solvents, where present, is/are removed.Subsequently, the adhesive layer is provided with a suitable protectivelayer.

The invention is further illustrated by the following examples:

Example 1 (Comparison example)

238 g of a self-crosslinking, acid (acid number of the dried mass ca.40) acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate andacrylic acid (47,85% in a solvent mixture of isopropanol, ethyl acetate,heptane, toluol and acetyl acetone 26:37:32:4:1), 50 g triglycerides ofthe caprylic/capric acids, 16 g physostigmine base and 20 g ethylacetate are mixed while stirring.

Then 20 g of a cationic copolymerisate on the basis ofdimethylaminoethyl methacrylate and neutral methacrylic esters, arestrewn into the mixture while stirring. Under elimination of light themixture is stirred for 8 hours at room temperature until completedissolution and the resulting solution is coated by means of a coatingknife onto an aluminized and siliconized polyethylene film.

After removal of the solvent by drying for 20 minutes at 60° C., theadhesive film is covered with a polyester film of 15 μm. Usingappropriate cutting tools, a size of 10 cm² is punched out and thelatticed edges are removed.

The stability of the active substance in the system was shown by way ofcontent determinations immediately after the manufacture and after3-months' storage, respectively. In this connection, neither thedecomposition products eseroline and rubreserine, known from theliterature, nor other decomposition products which have so far not beendescribed, could be detected. The physostigmine content corresponded tothe theoretical value. The method used was as follows:

Preparation of the samples:

1 plaster with covering foil is divided into four parts by means of apair of scissors; the covering foil is removed and is shaken, togetherwith the plaster sections, for at least 2 hours in a glass vessel whichis capable of being closed and is protected from light, with 50,0 mltetra-hydrofurane (p.a.), then subjected to ultrasonic treatment for 10min and subsequently centrifuged. Dilution for HPLC with methanol; andfurther centrifugation. Thereafter, the content of physostigmine in thecentrifugate is determined by HPLC.

Example 1 has a lipophilic matrix, due to the use of triglycerides. Itwas chosen in order to obtain a standard the stability of which could beused as a measure for the stability of examples 2-17.

Examples 2-17 were prepared according to the same method as example 1.Instead of neutral oil DAB 9, higher alcohols with 6 to 20 carbon atomswere used as softeners. Examples 15 and 16 are not examples inaccordance with the present invention. When using these alcohols,decomposition of the physostigmine occurs.

The qualitative and quantitative compositions of the matrices afterremoval of the solvent are shown in Table 2 hereinbelow. Aftermanufacture and after storage at 25° C. and 40° C., respectively, thesamples were examined according to the same method as in example 1. Adecomposition of the product could not be detected--except in the caseof examples 15 and 16, which are not in accordance with the invention.

                  TABLE 2                                                         ______________________________________                                        Composition of the Matrices                                                          Acid     Basic                                                                Poly-    Meth-   Physo-                                                Example                                                                              acrylate acrylate                                                                              stigmine Softeners                                    ______________________________________                                        2      67%      10%     8%       15%  1-hexanol                               3      67%      10%     8%       15%  1-heptanol                              4      67%      10%     8%       15%  1-octanol                               5      67%      10%     8%       15%  1-decanol                               6      67%      10%     8%       15%  1-nonanol                               7      67%      10%     8%       15%  1-undecanol                             8      77%      10%     8%       5%   1-dodecanol                             9      67%      10%     8%       15%  1-dodecanol                             10     62%      10%     8%       20%  1-dodecanol                             11     67%      10%     8%       15%  1-tetradecanol                          12     67%      10%     8%       15%  1-pentadecanol                          13     67%      10%     8%       15%  1-heptadecanol                          14     72%      10%     8%       10%  1-dodecanol                             15     67%      10%     8%       15%  propane diol                            16     67%      10%     8%       15%  glycerin                                17     57%      10%     8%       25%  1-octyl                                                                       dodecanol (1)                           18     67%      10%     8%       15%  1-oleyl                                                                       alcohol                                 ______________________________________                                         acid polymer: acrylate copolymer of 2ethylhexyl acrylate, vinyl acetate       and acrylic acid (AV of the dried pressuresensitive adhesive: ca. 40)         basic methacrylate: cationic copolymerisate on the basis of                   dimethylaminoethyl methacrylate and neutral methacrylic esters (KOH value     ca. 180)                                                                      1Nonadecanol and 1eicosanol could not be incorporated under these             conditions.                                                              

The adhesive forces were determined by way of experiments in accordancewith the Test Specifications AFERA 4001 P. 11. The term adhesive forcein this connection is used in the sense of the measured force necessaryfor peeling off a test sample having an area of 16 cm² from a steelplate at an angle of 90°. Each of the values stated is a mean value fromdeterminations with five test samples at a time. In this connection, itis known to the skilled artisan that a good adhesive performance onhuman skin is mostly observed in those cases where TTS according toAFERA exhibit good adhesive behaviour.

                  TABLE 3                                                         ______________________________________                                        Adhesive force of the systems in dependence on                                the chain length of the softeners used as alcohols                            Example    Softener     Adhesive Force  N!                                    ______________________________________                                        1          25% triglycerides                                                                          3.01                                                             of medium-chain                                                               fatty acids DAB 9                                                  2          15% 1-hexanol                                                                              9.89                                                  3          15% 1-heptanol                                                                             9.73                                                  4          15% 1-octanol                                                                              5.70                                                  5          15% 1-nonanol                                                                              9.35                                                  6          15% 1-decanol                                                                              6.16                                                  7          15% 1-undecanol                                                                            5.13                                                  9          15% 1-dodecanol                                                                            5.53                                                  11         15% 1-tetradecanol                                                                         2.52                                                  12         15% 1-pentadecanol                                                                         1.03                                                  13         15% 1-heptadecanol                                                                         0.42                                                  ______________________________________                                    

It can be seen from Table 3 that only the systems 11-13 exhibit a loweradhesive force than example 1. Furthermore, it is evident that as thechain lengths of the alcohols employed as softeners increase, theadhesive force becomes lower (the only exceptions are examples 3 and 7).

                  TABLE 4                                                         ______________________________________                                        Adhesive force seen in dependence on the portion of acid polyacrylate                              Adhesive                                                 Example  1-Dodecanol Force  N!                                                                              Acid Polyacrylate                               ______________________________________                                        8         5%         7.65     77%                                             14       10%         6.34     72%                                             9        15%         5.53     67%                                             10       20%         4.87     62%                                             ______________________________________                                    

It is evident that the adhesive force increases with the rising portionof acid polyacrylate.

                  TABLE 4a                                                        ______________________________________                                        Example   Softener      Adhesive Force  N!                                    ______________________________________                                        15        15% propane diol (1,2)                                                                      13.27                                                 16        15% glycerin  12.74                                                 ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        HLB values of the softeners                                                                                 HLB = 20                                                  M     Mo                                                                                           ##STR1##                                       ______________________________________                                        triglycerides of                                                                          ca. 504 M - 6 × 16 = 408                                                                      1.0*                                        medium-chain                                                                  fatty acids DAB 9                                                             methanol    32.04   15.03         10.6                                        ethanol     46.07   29.06         7.4                                         isopropanol 60.10   43.0          5.7                                         hexanol     102.18  85.17         3.3                                         heptanol    116.20  99.19         2.9                                         octanol     130.22  113.21        2.6                                         nonanol     144.24  127.23        2.4                                         decanol     158.26  141.25        2.2                                         undecanol   172.28  155.27        2.0                                         dodecanol   186.3   169.29        1.8                                         tetradecanol                                                                              214.34  197.33        1.6                                         pentadecanol                                                                              228.36  211.35        1.5                                         heptadecanol                                                                              256.47  239.46        1.3                                         nonadecanol 284.73  267.25        1.2                                         eicosanol   298.55  281.54        1.1                                         2-octyl dodecanol                                                                         298.55  281.54        1.1                                         oleyl alcohol                                                                             268.47  251.46        1.3                                         glycerin    92.10   41.08         11.1                                        propane diol                                                                              76.10   42.09         8.9                                         ______________________________________                                         value according to DAB 9  German Pharmacopoeia, 9th ed.!, Commentary S        3399.                                                                    

What is claimed is:
 1. In a transdermal therapeutic system for theadministration of physostigmine to the skin, consisting of a backinglayer impermeable to active substance, a pressure-sensitive adhesivereservoir layer containing 40 to 90 percent by weight polymeric materialand 0.1 to 20 percent by weight physostigmine base or a pharmaceuticallyacceptable salt thereof, and a removable protective layer covering thereservoir layer, the improvement wherein the base material of thereservoir layer is polymeric material based on an acrylate and/ormeth-acrylate and 0.1 to 40 percent by weight of a hydroxylgroup-containing softener having an HLB value between 1.1 and 12.0, withthe proviso that the softener is one which does not cause disintegrationof the physostigmine base or salt thereof.
 2. Transdermal therapeuticsystem according to claim 1, wherein the reservoir layer contains aspolymeric material acrylate copolymers of 2-ethylhexyl acrylate, vinylacetate and acrylic esters.
 3. Transdermal therapeutic system accordingto claim 1, wherein the polymeric material based on methacrylatescontains a copolymer based on dimethylaminoethyl methacrylate andneutral methacrylic esters.
 4. Transdermal therapeutic system accordingto claim 1, wherein the softener is 1-dodecanol.
 5. Transdermaltherapeutic system according to claim 1, wherein the softener is 2-octyldodecanol.
 6. Transdermal therapeutic system according to claim 1,wherein the softener is oleyl alcohol.
 7. Transdermal therapeutic systemaccording to claim 1 wherein the softener is a linear or branched,saturated or unsaturated alcohol having 6 to 20 carbon atoms.
 8. Aprocess for the production of a transdermal therapeutic system accordingto claim 1, comprising applying, to an impermeable backing layer, apressure-sensitive adhesive reservoir layer containing 40 to 90 percentby weight pressure-sensitive adhesive polymeric material and 0.1 to 20percent by weight physostigmine base or a pharmaceutically acceptablesalt thereof as active substance, and covering said layer with aremovable protective layer, wherein for the reservoir layer there isused a homogeneous mixture of a polymer material based on an acrylateand/or methacrylate, and 0.1 to 40 percent by weight of a hydroxylgroup-containing softener having an HLB-value between 1.1 and 12.0 withthe proviso that the softener is one which does not cause disintegrationof the physostigmine base or salt thereof.
 9. Process according to claim8, wherein the active substance is homogeneously mixed together with thecomponents of the adhesive reservoir layer, optionally in solution, andspread onto the backing layer impermeable to active substance,whereafter the solvent or solvents--where present--are removed and,subsequently, the adhesive layer is covered with a protective layer,whereafter the laminate is manufactured into individual TTS byseparating, which TTS are sealed into a packaging.